This disclosure provides Lectin-like oxidized low density lipoprotein receptor-1 (LOX1) binding proteins and methods for the use of such binding proteins, e.g., for the treatment, prevention and/or amelioration of a disease or condition associated with LOX1 including, e.g., vascular dysfunction, atherosclerosis (plaque progression, rupture and/or thrombosis) coronary artery disease (CAD), ischemia (e.g., myocardial ischemia), infarction (e.g., myocardial infarction), stroke and acute coronary syndrome (ACS).
Atherosclerosis is a complex disease that results from the accumulation of lipids, macrophages and fibrous elements as lesions in the arterial wall. The lesions develop into complex plaques that narrow the artery lumen and are a focus of chronic inflammation. The plaques are vulnerable to rupture triggering thrombosis that results in adverse cardiovascular events including stroke and myocardial infarction. Atherosclerosis is the primary cause of coronary artery disease, stroke and peripheral vascular disease and therefore represents the most common cause of morbidity worldwide (World Health Organization 2011).
Lectin-like oxidized low density lipoprotein receptor-1 (LOX1) is a disulphide linked type II transmembrane protein. It was first identified as a major receptor of oxidized low density lipoprotein (oxLDL) (Kume et al., 70th Scientific Sessions of the American Heart Association Ser. 96, 1997). The receptor consists of a short N terminal cytoplasmic domain, transmembrane domain, neck domain and a C-type lectin domain (CTLD), with the structure of the CTLD has been solved (Ohki et al., Structure 13:905-917 (2005)). In addition, LOX1 can be proteolytically cleaved in the neck domain releasing soluble LOX1 (sLOX1). LOX1 is a class E scavenger receptor and binds multiple ligands including oxLDL, C-reactive protein (CRP), phosphatidylserine, advanced glycation end products (AGEs), small dense lipoproteins (sdLDL), oxidized HDL, N4-oxononanoyl lysine (ONL), heat shock proteins (hsp), Chlamydia pneumoniae, platelets, leukocytes and apoptotic cells. Many of these ligands, particularly oxLDL, are associated with atherosclerosis. Multiple signal transduction pathways are associated with LOX1 activation including RhoA/Rac1, nitrogen monoxide, p38MAPK, protein kinase B and C, ERK1/2, and NFκB. See, e.g., Taye et. al., Eur J Clin Invest. 43(7):740-5 (2013).
Preclinical evidence implicates LOX1 in the promotion of vascular dysfunction, plaque progression, rupture and thrombosis, atherosclerosis and inflammatory conditions. See, e.g., Ulrich-Merzenich et al., Expert Opin Ther Targets. 17(8):905-19 (2013). For example, whereas LOX1 knockout mice have reduced aortic atherosclerosis and decreased vessel wall collagen deposition (Mehta et al., Circ. Res. 100:1634-1642 (2007)), LOX1 overexpression increased atherosclerotic plaque formation (Inoue et al., Circ. Res. 97:176-84 (2005); and White et al., Cardiovascular pathology 20:369-73 (2011)) with LOX1 expression observed on the vulnerable plaque shoulders and associated with macrophage accumulation, apoptosis, and MMP-9 expression (Li et al., Cir. Cardio. Imaging 3:464-72 (2010)). Neutralizing LOX1 antibodies restored acetylcholine induced coronary arteriolar dilation (Xu et al., Arterioscler. Thromb. Vasc. Biol. 27(4) 871-877 (2007)) and reduced intimal thickening after balloon injury in rats (Hinagata et al., Cardiovasc. Res. 69:263-71 (2006)). LOX1 expression in humans is not constitutive but dynamically inducible by proinflammatory stimuli. In the atherosclerotic plaque LOX1 is expressed on endothelial cells, smooth muscle cells and macrophages. Interestingly serum sLOX1 has been proposed to be diagnostic of plaque instability and rupture in acute coronary syndrome (ACS) patients (Nakamura et al., J. Pharm. Biomed. Anal. 51:158-163 (2010)); to be predictive of ACS recurrence or death (Kume et al., 70th Scientific Sessions of the American Heart Association Ser. 96, 1997); and is associated with increasing number of complex lesions (Zhao et al., Clin. Cardiol. 34:172-177 (2011)).
Atherosclerosis related mortality continues to rise due to the increasing prevalence of hypertension, diabetes, dyslipidemia and life-style characteristics (such as smoking and obesity) which are risk factors for atherosclerosis. Intervention with standard of care treatments including: platelet inhibitors, anti-hypertensives, HMG CoA reductases inhibitors (statins), thrombolytic agents, percutaneous arterial dilation, stenting or coronary artery bypass surgery have had significant clinical benefit. However, despite the use of preventative strategies and treatment there are still large numbers of patients who suffer from secondary major adverse cardiovascular events (MACE). Therefore there is a need for new therapeutics that can be used alone or in combination with the standard of care.